Sudden infant death syndrome (SIDS) is a leading cause of death under one year of age. Inspite of numerous investigations, the etiology and pathogenesis of SIDS remains unknown. The most widely accepted hypothesis suggests that in SIDS there is a defect in respiratory control mechanism. Although several line of evidence support this hypothesis, the precise nature of such a defect has not been defined. We have previously described in cases of SIDS specific changes in neural structures concerned with control of respiration (brain stem, vagus nerve) and more recently found elevated levels of catecholamines (CA), mainly dopamine in carotid bodies (CB) of SIDS infants. The latter suggests not only that CN function may be defective in SIDS infants, but that there may be a generalized neurotransmitter defect involving the catecholaminergic system. We have further characterized yet another peripheral chemoreceptor system located in intrapulmonary airways (neuroepithelial bodies, NEB) and propose that these sensors complement CB function and may be important for initiation of breathing at birth. These studies and observations clearly show that in SIDS potential defect(s) in control of respiration may involve some or all of its components. We postulate that one possible explanation for these defect(s) may be structural and biochemical immaturity of this control mechanism. Our research proposal is a mulitdisciplinary collaborative project focusing on neuroanatomical, biochemical and developmental aspects of respiratory control in SIDS. Our specific aims and objectives are: (1) To perform detailed and comprehensive morphologic and biochemical study of all components (central and peripheral) of respiratory control mechanism in the same cases of SIDS to be compared and contrasted with control infants (age-matched, different stages of development, chronically hypoxic infants). Combination of morphologic, morphometric, immunohistochemical and biochemical (for neurotransmitters, mainly CA) methods will be used for study of (a) central (neural) components (ie. forebrain, brainstem, vagus and phrenic nerves) and (b) peripheral (chemoreceptor) components (ie. CB and pulmonary NEB). This should reveal if in SIDS there is a consistent defect involving one or several components of respiratory control mechanism; if correlation exists between morphologic and biochemical abnormalities; and whether the defect(s) is related to immaturity of this system. (2) Experimental studies (in vitro and in vivo) will examine the role of chemosensory cells is regulation of breathing and during development. In vitro models of isolated CB and NEB cells from rabbits, will be used for direct studies on these cells and their responses to specific stimuli ie. hypoxia, nicotine - factors thought to play a role in pathogenesis of SIDS. The maturation of CB chemoreflex, the chemoreceptor function of NEB and forebrain influences on respiratory control will be studied in fetal and newborn lamb model. This is a separately funded project highly relevant to SIDS and complements our morphologic and biochemical studies on SIDS infants. We are ideally placed to perform this comprehensive study of respiratory control, since our research group includes expertise in all relevant fields and our institution has a direct access to large numbers of SIDS, control cases and other pediatric material. The findings of this study may not only lead to better understanding of the pathogenesis of SIDS, but may result in practical benefits, assuming identification of a specific biochemical (neurotransmitter) abnormality. If this assumption is correct then there is a hope in future to develop diagnostic test for SIDS and means for treatment and prevention of this disorder.